MicroRNAs in ALS: small pieces to the puzzle

Abstract

MicroRNAs have emerged as crucial regulators of neuronal function, suggesting that aberrant microRNA expression might contribute to pathologies of the nervous system. In this issue of The EMBO Journal, Emde et al (2015) report a global decrease in microRNAs as common hallmark of different forms of amyotrophic lateral sclerosis (ALS). Strikingly, enhancing microRNA biogenesis has beneficial effects on the neuromuscular function in mouse models of ALS. Thus, the microRNA pathway represents a promising novel target for therapeutic intervention in neurodegeneration.

Figure 1. Potential link between dysregulated miRNA biogenesis and ALS

(A) Under normal physiological conditions, pre‐miRNAs are by default processed by the Dicer complex in the cytosol. The resulting mature miRNA binds to specific target mRNAs, thereby blocking protein production. Interactions of Dicer with RBPs (e.g. TDP‐43) can enhance miRNA biogenesis. (B) In ALS, mutations in multiple genes (including TDP‐43, FUS, and SOD1) have been found to activate a stress response involving phosphorylation of eIF2α and SG formation. Remodeling of the Dicer complex leads to reduced pre‐miRNA processing and concomitantly decreased miRNA levels. As a consequence, the translation of target mRNAs is aberrantly relieved from inhibition by miRNAs, ending in degeneration of motor neurons.